Soluble, pre-fibrillar oligomeric tau (oligo-tau) has been identified as a major source of neurodegeneration in tauopathies. Injection of oligo-tau in wild-type and transgenic mice induces tau pathology, and propagates toxicity through cell-to-cell transmission. Antibodies specific to oligo-tau are an essential tool for mechanistic studies, and potential tools for diagnostic biomarkers as well as therapeutic intervention. This proposal aims to address three major limitations in existing anti-oligo-tau antibodies. First, all known oligo-tau antibodies are mouse immunoglobulins. This limit translating existing results from oligo-tau antibodies in humans, in particular to study antibody-mediated inhibition of cell-to-cell transmission. Second is the lack of high affinity oligo-tau antibodies. In mouse models of AD, only a small fraction of tau is oligomerized, and it is estimated that even smaller fraction would be found extracellularly. Antibodies that can engage these trace amounts of oligo-tau would lead to detection in clinical samples and potentially inhibition of cell-to-cell transmission. Finally, further distinction of oligo-tau species based on molecular signature would be necessary. Many distinct toxic soluble tau strains are known to exist in brain homogenates, and they induce distinct patterns of pathology and propagation. In particular, considering that post-translational modifications (PTMs) such as site-specific phosphorylation and acetylation have been also associated with disease progression, classifying oligo-tau based on PTM state would lead to novel insights. This proposal aims to address these challenges by developing high affinity human antibodies targeting oligo-tau. Based on the evidence that existing oligo- tau specific or conformation-specific antibodies recognize discontinuous epitopes, we hypothesize that recognizing discontinuous epitopes within tau would be critical for oligomer specificity. We will develop a novel antibody engineering strategy that mimics the somatic hypermutation process to enable the recognition of discontinuous epitopes, leading to high affinity without compromising antibody specificity.